chr5-13844998-A-G

Position:

• chr5-13844998-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001369.3(DNAH5):​c.5115-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.363 in 1,611,676 control chromosomes in the GnomAD database, including 108,496 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (12597 hom., cov: 32)
  • Exomes 𝑓: 0.36 (95899 hom.)
• Consequence: DNAH5 NM_001369.3 splice_region, intron
• Scores: Splicing: ADA: 0.00003832
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.128

Genes affected

DNAH5 (HGNC:2950): (dynein axonemal heavy chain 5) This gene encodes a dynein protein, which is part of a microtubule-associated motor protein complex consisting of heavy, light, and intermediate chains. This protein is an axonemal heavy chain dynein. It functions as a force-generating protein with ATPase activity, whereby the release of ADP is thought to produce the force-producing power stroke. Mutations in this gene cause primary ciliary dyskinesia type 3, as well as Kartagener syndrome, which are both diseases due to ciliary defects. [provided by RefSeq, Oct 2009]

DNAH5 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 5-13844998-A-G is Benign according to our data. Variant chr5-13844998-A-G is described in ClinVar as [Benign]. Clinvar id is 163149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13844998-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.589 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.5115-5T>C		splice_region_variant, intron_variant		ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.5115-5T>C		splice_region_variant, intron_variant		1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1	c.5070-5T>C		splice_region_variant, intron_variant				ENSP00000505288.1

Frequencies

GnomAD3 genomes AF: 0.401 AC: 60853 AN: 151824 Hom.: 12578 Cov.: 32

Gnomad AFR AF: 0.498

Gnomad AMI AF: 0.416

Gnomad AMR AF: 0.371

Gnomad ASJ AF: 0.347

Gnomad EAS AF: 0.607

Gnomad SAS AF: 0.347

Gnomad FIN AF: 0.315

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.353

Gnomad OTH AF: 0.398

GnomAD3 exomes AF: 0.379 AC: 94931 AN: 250624 Hom.: 18785 AF XY: 0.372 AC XY: 50483 AN XY: 135546

Gnomad AFR exome AF: 0.502

Gnomad AMR exome AF: 0.363

Gnomad ASJ exome AF: 0.341

Gnomad EAS exome AF: 0.630

Gnomad SAS exome AF: 0.340

Gnomad FIN exome AF: 0.320

Gnomad NFE exome AF: 0.351

Gnomad OTH exome AF: 0.369

GnomAD4 exome AF: 0.359 AC: 524248 AN: 1459734 Hom.: 95899 Cov.: 36 AF XY: 0.358 AC XY: 259714 AN XY: 726308

Gnomad4 AFR exome AF: 0.497

Gnomad4 AMR exome AF: 0.369

Gnomad4 ASJ exome AF: 0.339

Gnomad4 EAS exome AF: 0.559

Gnomad4 SAS exome AF: 0.339

Gnomad4 FIN exome AF: 0.326

Gnomad4 NFE exome AF: 0.351

Gnomad4 OTH exome AF: 0.370

GnomAD4 genome AF: 0.401 AC: 60913 AN: 151942 Hom.: 12597 Cov.: 32 AF XY: 0.398 AC XY: 29538 AN XY: 74272

Gnomad4 AFR AF: 0.499

Gnomad4 AMR AF: 0.371

Gnomad4 ASJ AF: 0.347

Gnomad4 EAS AF: 0.607

Gnomad4 SAS AF: 0.346

Gnomad4 FIN AF: 0.315

Gnomad4 NFE AF: 0.353

Gnomad4 OTH AF: 0.396

Alfa AF: 0.364 Hom.: 5062

Bravo AF: 0.413

Asia WGS AF: 0.454 AC: 1576 AN: 3478

EpiCase AF: 0.349

EpiControl AF: 0.345

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	5115-5T>C in intron 31 of DNAH5: This variant is not expected to have clinical s ignificance because it has been identified in 49.9% (2200/4406) of African Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs4429853). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Primary ciliary dyskinesia Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 10, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

Primary ciliary dyskinesia 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.4
DANN	Benign	0.30

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4429853; hg19: chr5-13845107; COSMIC: COSV104595587;